Usefulness of Carcinoembryonic Antigen Determination in Bronchoalveolar Lavage Fluid* A Comparative Study among Patients with Peripheral Lung Cancer; Pneumonia, and Healthy Individuals Alfredo de Diego, M.D.; Luis Compte, M.D.; Jose Sanchis, M.D.; Maria jose Enguidanos, M.D.; and VICente Marco, M.D.

We compared carcinoembryonic antigen (CEA) levels in broncboalveolar lavage (BAL) 8uid and serum of patients with lung cancer, pneumonia, and healthy individuals to determine the usefulness of CEA in diagnosing lung cancer not visible endoscopicall~ Cancer patients had CEA lavage 8uid levels (4,650:t 1,565 nglmg of albumin) signi6candy higher than pneumonia patients (755:t 346 nglmg) or healthy individuals, smokers (1S!:t 48 nwml), and DOnsmokers (175:t6 nglmg). In serum, CEA assay cannot: discern between cancer (35:t 13 nglmI) and pneumonia (4.6:tl.4 nwml) (p=O.06). Using 1,000 nwmg of albumin as the cutting point in BAL 8uid, sensitivity and speci&city were 77 percent and 94 percent, respectivel~ In serum, 5 nwml provided a sensitivity of 55 percent and speci6city of

Fiberoptic bronchoscopy is the most effective technique to diagnose lung cancer. When the tumor is visible endoscopicall~ a positive diagnosis of cancer can be obtained in 98 percent of the cases. 1 However, in peripheral tumors, the diagnostic yield of endoscopic methods is usually lower, depending on tumor size and location. 2 Thus, the use of other complementary methods could be helpful. Biochemical or immunologic tumor markers have long been suggested as an aid in the diagnosis of cancer. 3 Carcinoembryonic antigen (CEA), a cell surface glycoprotein, is widely used and well accepted as an endodermal origin tumor marker. Serum levels are elevated in patients with carcinoma of the lung, 4 but they are also elevated in some benign lung diseases or in healthy smokers;5 thus, the CEA determination in serum has a limited value as a diagnostic test. 6 With the aim of increasing the sensitivity of the assa~ several authors7 •8 have proposed the determination of CEA in bronchoalveolar lavage (BAL) fluid of the affected lung. If sensitivity improved, its application in the diagnosis of patients with normal bronchoscopy findings could be very useful. In a preliminary stud~9 we showed that CEA levels ·From the Servicio de Neumologfa (Drs. de Diego, Com~te, Sancms, and Marco) and DepartaInento de Biopatologfa (Dr. Enguidanos), Hospital Universitario ccLa Fe;· Valencia, Spain. Manuscript received August 20; revision accepted Febrnary 15.

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91 percent. Positive and negative predictive values were 77 percent and 94 percent in BAL, respectively, and 6! percent and 89 percent in serum, respectively. Using a combination of serum and BAL 8uid CEA levels, the sensitivity and speci&city were 88 percent and positive and negative predictive values were 66 percent and 96 percent, respectively. When used in combination with serum levels of CEA or transbronchial biopsy, the diagnostic yield increased up to 88 percent. Thus, although CEA determination in BAL 8uid improves diagnostic yield, it should not be used as the only diagnostic procedure. (Chat 1991; 100:1060-63)

I

~ = e8rdn0embryooic antigen; TB = transbroochialluog bi-I

in BAL fluid were significantly higher in patients with lung cancer not visible endoscopically than in healthy subjects. However, to confirm the diagnostic value of CEA determination in BAL fluid of cancer patients, other lung diseases such as pneumonia should not cause a significant elevation of CEA concentration in BAL. In the present investigation, we have determined CEA level in BAL fluid ofpatients with uncomplicated pneumonia and compared these levels with those of patients with proved peripheral lung cancer. We chose patients with pneumonia because in a sizable number of cases, lung cancer is presented as a postobstructive pneumonitis. Results were also compared with healthy individuals, smoking and nonsmoking. Finall~ we analyzed if CEA determination in BAL increased the diagnostic yield of endoscopic methods. MATERIAL AND METHODS

Subjects

We studied 45 individuals, nine of whom were patients with peripheral lung cancer, nine had pneumonia, 16 were healthy smokers, and 11 were healthy nonsmokers. All of them were included in the study after personal informed consent and were well matched for age and cigarette consumption. There was only one nonsmoker in either cancer or pneumonia group. Demographic data are shown in 1llble 1. Healthy individuals, smokers and nonsmokers, were recruited among hospital personnel volunteers and outpatients undergoing

C8IdnoembIyonic Antigen Determination In BronchoaIYeoIar Lavage fluid (de DIego et 81)

Table l-DernogrGpIaic CluJrtJCferinicl offtJtientltmtl lletJlthy l~ Smo1cen, and NOfIIfIIObn

Cancer Pneumonia Smoken Nonsmoken

No.

Age, yr*

Smoking, PaclclYears*

M:FRatio

9 9 16 11

6O±3 56±4 43±4 52±4

26±4 2O±3 22±3 0

8:1 7:2 12:4 6:5

*Values are means±SD. fiberoptic bronchoscopy for penistent coughing of unbown origin, after other diseases such as rhinosinusitis, otitis, bronchitis, asthma, and gastroesophageal reflux had been excluded; most of them were diagnosed as psychogenic cough. Other pulmonary diseases were also excluded and results of clinical examination and chest roentgenography were normal in all cases. Subjects were included only if bronchoscopy was unrevealing and cytologic and bacteriologic examinations revealed no abnormalities. In patients with peripheral lung cancer, the definitive diagnosis was obtained by transbronchial lung biopsy in five patients and after surgery in the remaining four patients. Histologic cell types were as follows: squamous cell carcinoma, three patients; adenocarcinoma, five patients; and undifferentiated carcinoma, one patient. Patients with pneumonia were diagnosed by clinical symptoms and an image of alveolar consolidation on roentgenographic examination. The suspected responsible microrganism was isolated by culture of bronchial secretions obtained by means of a telescopic catheter. Methods

immunoassay (CEA-EIA Monoclonal One-Step; Abbott Laboratories, North Chicago, IL) following the instructions of the laborato~ In brief, samples are incubated at ~C with anti-eEA (mouse, monoclonal) coated beads, and anti-CEA (mouse, monoclonal) conjugated with honeradish peroxidase for 1 h. The beads are then incubated at moc with o-phenylenediamine for 30 min yielding a yellow-orange color. The enzyme reaction is stopped by the addition of 1 N sulfuric acid and the intensity of color developed is read using a spectrophotometer set at 492 nm. Appropriate standards of known concentrations ofCEA were run with every test to construct a standard curve. The CEA concentration in the samples is calculated from the standard curve. The sensitivity of the assay is 0.5 nglml. CEA concentrations in BAL were expressed as nanogram of CEA per milligram ofalbumin. We used albumin as the reference protein denominator assuming that it is diluted to the same degree as CEA by the instilled liquid. Albumin was determinated by radial immunodiftUsion using commercial plates (Kallestad Laboratories, Austin, TX). St4tUtical Analylis

All data are expressed as mean ± SEM. Using the KolmorowSmirnof test, we could not assume the normality of the distribution of CEA concentrations in serum or lavage fluid of the control group. Therefore, the significance of differences between groups was assessed by the Mann-Whitney U test. A probability value ofO.OS was considered significant. The correlation coefBcient of Spearman was used to assess an association between some parameters. To analyze the sensitivity, specificity, and predictive values of abnormal CEA levels, we used 2 x 2 contingency tables.

BAL was performed through a 6beroptic bronchoscope (Olympus BFI0; Olympus Corp, New Hyde Park, NY). The bronchoscope was introduced transnasally and wedged into the affected lung segment. In normal subjects, it was introduced in the middle lobe. Then, three aliquots of 50 ml of sterile normal saline solution, at room temperature, were instilled and aspirated gently by syringe. The aspirate of the ftnt aliquot, which contains most of the mucous secretions and cellular debris, was discarded; the mean fluid recovery of the two other aspirates was 60 percent of the instilled saline solution. The lavage fluid obtained was 6ltered through a double layer of surgical cotton gauze and then centrifuged for 20 minutes at 500 X g to separate the cell pellet. The supernatant was decanted and stored at - moe until analysis. The cell pellet was resuspended in Hanks' solution and submitted for cytologic diagnosis. At the time of bronchoscopy, 10 ml of venous blood was taken, allowed to clot, and centrifuged to obtain serum that was stored at

RESULTS

Lavage and serum CEA results for all the groups are presented in Table 2. There were no significant differences in albumin BAL levels among groups, thus allowing us to make accurate comparisons of CEA in lavage fluid. We found no correlation among age, cigarette consumption, and CEA levels in any of the groups. Patients with cancer had CEA lavage fluid levels significantly higher than patients with pneumonia, in absolute values (p

Usefulness of carcinoembryonic antigen determination in bronchoalveolar lavage fluid. A comparative study among patients with peripheral lung cancer, pneumonia, and healthy individuals.

We compared carcinoembryonic antigen (CEA) levels in bronchoalveolar lavage (BAL) fluid and serum of patients with lung cancer, pneumonia, and healthy...
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